Transcript Slide 1

Undiagnosed Conn’s Syndrome in Greater
Auckland
a mini-epidemic?
Conn’s Syndrome (primary aldosteronism)
A secondary cause of hypertension associated with aldosterone excess
Autonomous aldosterone hypersecterion
Volume-dependent hypertension/ renin suppression
50% normokalaemic
Aetiology
APA – 1/3
BAH – 2/3
(hereditary forms including GRA constitute a rare subset of BAH)
Treatment
APA – unilateral adrenalectomy or spironolactone
BAH – spironolactone
Standard NZ work-up for Conn’s
Resistant hypertension + hypokalaemia
↓
Check renin and aldosterone (with or without discontinuation of drugs particularly
spironolactone, and possibly beta blocker)
↓
PA suggested if aldosterone/renin ratio (pmol/l/ mU/l) > 55, providing aldosterone >
400pmol/l
↓
Confirmatory test is saline suppression test
(Check baseline aldosterone, then infuse 2000ml iv 0.9% NaCl over 4 hours the recheck
aldosterone – if post-infusion aldosterone > 165pmol/l, PA is confirmed)
↓
Adrenal CT
↓
Obvious lipid rich adenoma > 1cm
↓
Laparoscopic adrenalectomy
↓
normal or equivocal
↓
Either treat medically or consider AVS
Journal of Hypertension- Open Access
2014;3(1)
Should all Hypertensive Patients be Screened for Primary
Aldosteronism?
Chan PL, van der Merwe W, van der Merwe V
635 consecutive patients seen at the
hypertension clinic (March 2009- Dec 2012)
 58% female
 Average age 59 (female) 52 (male)
 Mean BMI 29
 Mean 1st visit BP 154/85 – on 2.6 drugs
 Mean discharge BP 130/76 – on 2.9 drugs
 Average clinic visits 3
 At discharge 178/ 635 had fulfilled the strict JNC-7 criteria for
the diagnosis of “resistant hypertension”
All patients screened for PA except
 those not requiring drugs (prehypertension, white
coat hypertension)
 very elderly
 BP rapidly responsive to simple medication
453/635 (71%) had renin and aldosterone checked
on at least 1 occasion
Results
6 confirmed and 2 probable cases of PA (8)
4 APA
- 3 adrenalectomies
- 1 chose long term spironolactone in preference
2 BAH (proven with AVS)
- long term spironolactone treatment
2 very likely PA but inx not completed due to old age and comorbidites
- both had excellent response to empirical spironolactone treatment
ALL 8 CASES HAD RESISTANT HYPERTENSION AND PROVOKED OR
UNPROVOKED HYPOKALAEMIA
8/635 = 1.25% incidence in general hypertension clinic
population
All of the confirmed cases had resistant hypertension
8/178 = 4.5% incidence in resistant hypertension clinic
population
“ Routine screening for PA is not warranted in the general
hypertensive population and should probably be
confined to those who have both resistant hypertension
and provoked or unprovoked hypoklaemia”
Is that right or are we missing heaps?
Is There an Unrecognized Epidemic of Primary
Aldosteronism? (Pro)
David A Calhoun
Hypertension. 2007;50:447-453
Is There an Unrecognized Epidemic of Primary
Aldosteronism? (Con)
Norman Kaplan
Hypertension. 2007;50:454-458
Prevalence of primary aldosteronism in patients according to Sixth Joint National
Committee (JNC VI) stages of severity of hypertension (stage 1, 140 to 159/90 to 99
mmHg; stage 2, 160 to 179/100 to 109 mmHg; stage 3, ≥180/110 mmHg) (20).
Calhoun D A CJASN 2006;1:1039-1045
©2006 by American Society of Nephrology
Prevalence of primary aldosteronism in patients with resistant hypertension from multiple
clinics worldwide (25–28).
Calhoun D A CJASN 2006;1:1039-1045
©2006 by American Society of Nephrology
Lumpers
Splitters





As long as their BP is
effectively treated who cares if
the diagnosis of PA is made or
not?
The obvious ones will declare
themselves
Many pts with difficult
hypertension will end up on
spironolactone anyway and
some of these may have
undiagnosed PA.
Pts with APA, especially older
pts on multiple drugs, often
still require some drugs to
control their BP postadrenalectomy, so why bother
with surgery


Patients with undiagnosed PA
do worse on conventional BP
meds even if their BP is
controlled
Laparoscopic adrenalectomy
for APA is one of the few truly
curable causes of hypertension
and pts deserve the
opportunity of knowing if they
are a candidat for this
procedure.
Empirical use of
spironolactone in resistant
hypertension is not always
well-tolerated and many men
find the anti-androgenic side
effects difficult.
Cardiovascular outcomes in patients with
primary aldosteronism after treatment
Catena C et al
Arch Intern Med 2008;168:80-85
Long-term renal outcomes in patients with
primary aldosteronism.
Sechi L, Novello M, Lapenna R
JAMA 2006;295:2638-2695
HYPOTHETICAL MODELLING
Greater Auckland Population (CMDHB + ADHB + WDHB) ~ 1 540 000
↓
Of whom “adults” (>= 18 years) ~ 1 124 200
↓
Among whom hypertension prevalence ~ 292 300 (26%)
↓
Annual incidence (new cases) ~ 20370 (1.8% of adult population)
↓
Expected (minimum) incidence of PA
↓
407 new cases annually
↓
135 APA/ 271 BAH
No registry,
database, or
formal data
collection
How many cases of Conn’s Syndrome did you diagnose in
calender year 2013 (APA + BAH)?
19 endocrinologists surveyed/ 13 responded
7 - no cases
1 – 2 cases
3 - 1 case
1 - 1 case in the past 2 years
1 - Don’t keep count
6 – no response
Total confirmed cases 6 (or 7 if we allow 1 for the one who
doesn’t keep count)
1.54 million people in the 3 Auckland DHB’s – 6 or 7 cases
of PA diagnosed by endocrinologists in 2013
On the presumption that we were missing
many cases, in 2013 our clinic adopted
much more rigorous screening and
diagnostic guidelines for PA
↓
Audit of all PA diagnoses in calendar year
2013
Waitemata 2013 Hypertension Clinic Audit
328 new patients seen between 7 Jan and 28
Dec 2013
Similar demographics to previous survey
WDHB 2013 Hypertension Clinic Audit
APA adrenalectomy - 6
APA awaiting adrenalectomy - 3
BAH proven with AVS - 7
Probable PA but inx incomplete
•non compliance - 2
•severe renal failure – 2
Total 20 (8 normokalaemic and some did not fulfil criteria
for resistant hypertension)
Diagnostic rate for all increased from 1.25% in
earlier survey (4.5% of those with resistant
hypertension)
to
6% for all in current survey (~ 18% of those with
resistant hypertension**) – incidence about 4x
greater than in the previous survey
** Not all diagnosed PA in this survey had
resistant hypertension and a significant
minority had no history of provoked or
unprovoked hypokalaemia
Reasons the diagnosis is missed
• Aldosterone measurements profoundly affected by serum K+
• Failing to appreciate that > 50% of Conns are normokalaemic
• Failing to appreciate the significance of provoked hypokalaemia
• Failure to check renin and aldo
• Labelling renin and aldo levels as “normal”
• Failing to repeat renin and aldo on several occasions in the event of discrepant results
• Over-emphasis on the ratio, overemphasis on raised aldosterone
• Failing to account for drug effects on renin/ aldo measurements
• Radiologists misreporting scans (missing small adenomas – with CT, lack of
retroperitoneal fat makes visualisation difficult)
• Saline suppression test no good
• 24 hour urine aldo no good
• Labelling pts “probable BAH” and failing to proceed to AVS
• Presuming that missing the diagnosis of Conn’s does not matter provided BP is
controlled
Screening for PA in hypertensive
patients
At first visit check plasma renin,
aldosterone, and electrolytes on existing
medication
(if on no medication, do not start any drugs
until results available)
PRA 1ng/ml/hr = plasma renin 8.4mu/l
(multiply by 8.4)
Aldosterone 1ng/dl = 27.7pmol/l (multiply
by 27.7)
The patients with results highlighted in red require further evaluation
No drugs + hypertension
K < 3.5, renin < 8.2, aldo > 416 (very likely PA)
K < 3.5, renin < 8.2, aldo > 165 (likely PA)
K < 3.5, renin < 8.2, aldo < 165 (possible PA)
K > 3.5, renin < 8.2, aldo > 165 (possible PA)
K > 3.5. renin < 8.2, aldo < 165 (very unlikely PA)
K < 3.5, renin > 8.2, aldo (any) (very unlikely PA)
Thiazides + hypertension
K < 3.5, renin < 8.2, aldo > 416 (likely PA)
K < 3.5, renin < 8.2, aldo > 165 (possible PA)
K > 3.5. renin < 8.2, aldo < 165 (very unlikely PA)
K < 3.5, renin > 8.2, aldo > 165 (possible PA)
K > 3.5, renin > 8.2 aldo > 416 (possible PA)
ACE-inhibitors and CCB’s + hypertension
K < 3.5, renin < 8.2, aldo > 416 (very likely PA)
K < 3.5, renin < 8.2, aldo > 165 (likely PA)
K > 3.5. renin < 8.2, aldo > 165 (possible PA)
K > 3.5, renin > 8.2, aldo > 416 (possible PA)
Beta blockers + hypertension
K < 3.5, renin < 8.2, aldo > 165 (likely PA)
K > 3.5, renin < 8.2, aldo > 416 (possible PA)
K > 3.5. renin < 8.2, aldo < 165 (unlikely PA)
K > 3.5, renin > 8.2, aldo (any) (very unlikely PA)
Patients selected for further evaluation
↓
Discontinue spironolactone, beta blocker, thiazide, ( and if
possible ACE/ARB, and DHP-CCB)
↓
Temorarily replace (if necessary) with verapamil +/- doxazosin
+/- hydralazine
↓
Supplement with KCl as necessary to maintain normal serum K+
and encourage liberal sodium intake
↓
Wait several weeks
↓
↓
Midmorning renin, aldosterone and electrolytes
(seated 5 mins after at least 1 hour in upright position)
↓
Plasma renin < 8.4 mu/l warrants further
evaluation for PA, providing aldosterone >
165pmol/l and serum K+ >= 3.5mmol/l
(if serum K+ < 3.5mmol/l and aldosterone < 165pmol/l
the test is uninterpretable and needs to be repeated
after correcting potassium)
↓
Confirmatory Testing
“The Saline Suppression
Test Is Unreliable”
(concurs with my personal experience
and my reading of the literature..)
Outpatient Fludrocortisone Suppression Test (FST)
5 day
NaCl tabs 10mmol 3TDS + increase dietary sodium
Slow K 2 TDS (or more)
Fludrocortisone 0.1mg QID
Day 3 morning check U+E
If K < 3.5mmol/l increase Slow K to 3 TDS or QID
Wed 8am – Thurs 8am collect 24 hour urine sodium
Thursday morning (ideally mid-morning, seated 10-15 mins after
ambulation 1-2 hrs – supine position can reduce aldo level)
Collect blood for renin, aldo, and electrolytes
PA is confirmed if
Aldosterone is > 165pmol/l and renin < 8.2mu/l and serum K
> 3.5mmol/l)
Biochemically confirmed PA
↓
Request CT**
↓
Simultaneously request
adrenal vein sampling (AVS)
↓
Presence of an adenoma on CT does not obviate the need for
AVS
↓
Differentiation between APA and BAH made on AVS result
CT**
Waitemata Conn’s Protocol
Non contrast adrenals
↓
Split bolus arterial and venous contrast
(gives simultaneous V and A opacification)
•
hepatic, renal and adrenal veins
•
renal arteries
“Of the few innocent pleasures
remaining to men past middle life,
jamming common sense down the
throats of fools is surely the keenest”
TS Huxley
Acknowledgement
Prof Michael Stowasser (Brisbane) for
generously offered advice and support